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Updated: May 27, 2025
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Structural optimization and biological evaluation of indolin-2-one derivatives as novel CDK8 inhibitors for
Jui-Yi Hsu1, Kai-Cheng Hsu2, Ching-Hsuan Chou3
1Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Abstract:
Cyclin-dependent kinase 8 (CDK8) plays a crucial role in the transforming growth factor beta (TGF-β) signaling pathway, which is critical to the pathology of idiopathic pulmonary fibrosis (IPF). CDK8 promotes the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition, making it a promising target for IPF treatment. This study focused on optimizing F059-1017, a previously identified CDK8 inhibitor, to enhance its potency. Through integrated structure-based modifications, a series of compounds was synthesized, and their inhibitory effects on CDK8 were tested. Results indicated that substituting with cyclopentanone significantly improved the inhibitory activity, and compound 4j demonstrated the best potency (IC50 = 16 nM). Notably, compared to F059-1017, its potency increased 35-fold, and kinase profiling revealed that the compound was selective for CDK8. Compound 4j inhibited the TGF-β1-induced EMT, cell migration, and morphological changes in A549 cells at a concentration of 0.1 μM and inhibited ECM and EMT protein expressions. In addition, the compound blocked TGF-β1-induced transcriptional changes and inhibited Smad3 and RNA polymerase II phosphorylation. These results highlight the potential of the optimized CDK8 inhibitor as a prospective drug for IPF treatment.
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